We have previously established the 1 degree structure, expression and signaling properties of the human N-formyl peptide receptor (FPR), the FPRL1 receptor (FPRL= formyl peptide receptor like), interleukin-8 receptor type B (IL8RB), and the MIP-1alpha/RANTES receptor from cDNA and gene cloning. We have also previously defined the complete DNA sequence and structural organization of the human FPR gene including an analysis of its putative promoter sequence, and have proposed a mechanism for the molecular evolution of the FPR gene family. We have now cloned the gene and cDNA for the putative FPRL2 receptor which is 56% identical in amino acid sequence to FPR and 83% identical to FPRL1R, yet does not bind prototype N-formylpeptides such as N-formyl-met-leu-phe (fMLF). Unlike FPR and FPRL1R, whose RNAs are detectable in both normal human neutrophils and monocytes, the FPRL2 mRNA is detectable in monocytes but not neutrophils. We have also cloned the gene for the murine homologue of FPR and characterized its product as a low affinity receptor for fMLF. Analysis of chimeric FPR:FPRL1R receptors indicated that the high affinity binding site for fMLF is formed by the apposition of multiple non-contiguous extracellular domains. These data and sequence comparisons among the high and low affinity fMLF receptors have pointed to five residues that may be particularly important for high affinity ligand binding and signal transduction. We discovered that open reading frame ECRF3 of Herpesvirus saimiri encodes a protein with 33% amino acid sequence identity to IL8RB that is a functional receptor for the same ligands that activate IL8RB (IL-8, GRO/MGSA and NAP-2). The MIP- 1alpha/RANTES receptor also has a viral homologue, US28 of human cytomegalovirus. These findings contribute to an emerging theme in DNA virology whereby molecular mimicry of host defense proteins is accomplished by gene copying. We have previously shown that proteins involved in host defense functions are highly and exceptionally divergent between human and rodent species, and have proposed a new hypothesis to account for this phenomenon that has to do with molecular mimicry by acquisition of host genes by species-specific pathogens.